Am J Cancer Res. 2011;1(5):604-17. Epub 2011 Apr 15.
Prostate cancer, the most common male cancer in Western countries, is commonly detected with complex chromosomal rearrangements. Following the discovery of the recurrent TMPRSS2:ETS fusions in prostate cancer and EML4:ALK in non-small-cell lung cancer, it is now accepted that fusion genes not only are the hallmark of haematological malignancies and sarcomas, but also play an important role in epithelial cell carcinogenesis. However, previous studies aiming to identify fusion genes in prostate cancer were mainly focused on expression changes and fusion transcripts. To investigate the genes recurrently affected by the chromosome breakpoints in prostate cancer, we analysed Affymetrix array 6.0 and 500K SNP microarray data from 77 prostate cancer samples. While the two genes most frequently affected by genomic breakpoints were, as expected, ERG and TMPRSS2, surprisingly more known tumour suppressor genes (TSGs) than known oncogenes were identified at recurrent chromosome breakpoints. Certain well-characterised TSGs, including p53, PTEN, BRCA1 and BRCA2 are recurrently truncated as a result of chromosome rearrangements in prostate cancer. Interestingly, many of the genes residing at recurrent breakpoint sites have not yet been implicated in prostate carcinogenesis such as HOOK3, PPP2R2A and TCBA1. We have confirmed the generally reduced expression of selected genes in clinical samples using quantitative RT-PCR analysis. Subsequently, we further investigated the genes associated with the t(4:6) translocation in LNCaP cells and reveal the genomic fusion of SNX9 and putative TSG UNC5C, which led to the reduced expression of both genes. This study reveals another common mechanism that leads to the inactivation of TSGs in prostate cancer and the identification of multiple TSGs inactivated by chromosome rearrangements will lead to new direction of research for the molecular basis of prostate carcinogenesis.
前列腺癌是西方国家最常见的男性癌症，通常通过复杂的染色体重排来检测。在发现前列腺癌中的 TMPRSS2:ETS 融合和非小细胞肺癌中的 EML4:ALK 融合之后，现在人们已经接受了融合基因不仅是血液恶性肿瘤和肉瘤的标志，而且在上皮细胞癌变中也起着重要作用。然而，以前旨在鉴定前列腺癌中融合基因的研究主要集中在表达变化和融合转录本上。为了研究前列腺癌中染色体断裂点反复影响的基因，我们分析了 77 例前列腺癌样本的 Affymetrix 芯片 6.0 和 500K SNP 微阵列数据。虽然最常受基因组断裂点影响的两个基因是 ERG 和 TMPRSS2，但出乎意料的是，在反复出现的染色体断裂点中发现了更多的已知肿瘤抑制基因（TSGs）而不是已知癌基因。某些特征明确的 TSGs，包括 p53、PTEN、BRCA1 和 BRCA2，由于前列腺癌中的染色体重排而被反复截断。有趣的是，许多位于反复出现的断点部位的基因尚未涉及前列腺癌的发生，例如 HOOK3、PPP2R2A 和 TCBA1。我们使用定量 RT-PCR 分析在临床样本中证实了选定基因的普遍低表达。随后，我们进一步研究了与 LNCaP 细胞中 t(4:6)易位相关的基因，并揭示了 SNX9 和推定的 TSG UNC5C 的基因组融合，导致这两个基因的表达降低。这项研究揭示了导致前列腺癌中 TSG 失活的另一种常见机制，并且鉴定出多个通过染色体重排失活的 TSG 将为前列腺癌发生的分子基础的研究提供新的方向。
